Site-Selective Electrophilic Cyclization and Subsequent Ring-Opening

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Site-Selective Electrophilic Cyclization and Subsequent Ring Opening: A Synthetic Route to Pyrrolo[1,2-a]quinolines and Indolizines Trapti Aggarwal, Sonu Kumar, Devendra Kumar Dhaked, Rakesh K. Tiwari, Prasad V. Bharatam, and Akhilesh K. Verma J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo3015374 • Publication Date (Web): 05 Sep 2012 Downloaded from http://pubs.acs.org on September 10, 2012

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The Journal of Organic Chemistry

Site-Selective Electrophilic Cyclization and Subsequent Ring Opening: A Synthetic Route to Pyrrolo[1,2-a]quinolines and Indolizines Trapti Aggarwal,† Sonu Kumar,† Devendra K. Dhaked,‡ Rakesh K. Tiwari,†,§ Prasad V. Bharatam‡ and Akhilesh K. Verma,†,* †

Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi, 110007, India ‡

§

Department of Medicinal Chemistry, NIPER, Punjab (Mohali) -160062 India

Department of Biomedical & Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island, USA E-mail: [email protected]

Route A

OMe O R1

N

OMe

i. cat. Pd / base ii AgOTf (5 mol %)

5

R3

O R2

N

R1

I 2 R1 = H, OMe

3

3

i. cat. Pd / base

upto 92%

OMe O

O R2

N 2

Ea = 31.31 kcal/mol

a

R = Ph; R3 = Aryl

2

R = Aryl/Alkyl; R3 = Aryl

N R3

R2 Y

6, 7 (Y = H) 8, 9 (Y = I)

OMe

sonogashira N

O

ii AgOTf (5 mol %) 1 R or 3 equiv I2

R

electrophilic cyclization

O

Route B

Ea= 9.01 kcal/mol

b

3

4 R

electrophilic cyclization and ring opening

3

4 R

ABSTRACT: An efficient strategy for the synthesis of pyrrolo[1,2-a]quinolines and indolizines from pyranoquinolines via site-selective electrophilic cyclization and subsequent opening of 1 ACS Paragon Plus Environment


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pyran ring using silver/iodine under mild reaction conditions is described. This approach involves the preferential attack of the pyridyl nitrogen over aryl ring and leads to the formation of 5-endo-dig cyclized products. Quantum chemical calculations between C-N (ΔEa = 9.01 kcal/mol) and C-C (ΔEa = 31.31 kcal/mol) bond formation were performed in order to rationalize the observed site selectivity. Structure of the products were confirmed by the X-ray crystallographic

studies.

Iodo-substituted

compounds

generated

by

the

electrophilic

iodocyclization were further diversified via Pd-catalyzed cross-coupling reactions.

INTRODUCTION The simplicity, efficiency and generality of the transition-metal-catalyzed tandem reactions1 have led to its applications in the synthesis of a wide variety of heterocyclic/carbocyclic compounds and natural products. Nitrogen-containing heterocycles and their analogues are pharmaceutically important scaffolds.2 During the past decade, pharmacological prospectives of the pyrrolo[1,2-a]quinolines3 and indolizines4 has been well recognized due to their potential biological activity and presence in many natural alkaloids. Some of the pyrrole-fused heterocycles, such as dihydroisoquinolines have shown in vivo activity against P388 leukemia5 (Figure 1). The nucleus of indolizine derivatives are associated with a wide range of biological activities including anticancer,6 antibacterial,3a antifungal,7 anti- tubercular8 and anti-histaminic9, cytotoxic and CNS depressant activity10 (Figure 1). Although numerous methods are available for the synthesis of pyrrolo[1,2-a]quinoline11 and indolizines,12 new strategies to synthesize these class of scaffolds with high molecular diversity are highly in demand. Halogenated heterocyclic compounds serve as a useful platform for increasing the molecular diversity.13 In this context, the reactions incorporating halogens like 2 ACS Paragon Plus Environment

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iodocyclization14,15 are highly valuable. The introduction of iodide functionality in the molecule provide avenue for further synthetic elaboration.

Figure 1. Selected examples of biologically relevant pyrrolo-quinolines and indolizines In 2007, Gevergyon and co-workers16 reported the synthesis of pyrroloquinolines and indolizines by the metal-catalysis (Scheme 1, eq 1). While, recently Kim and co-workers17 reported the synthesis of indolizines by 5-endo-dig iodocyclization (Scheme 1, eq 2). To the best of our knowledge, cyclization followed by ring opening has not been explored. Herein, we reported the synthesis of highly functionalized pyrrolo[1,2-a]quinoline

and indolizines via

silver-catalyzed as well as iodine-mediated 5-endo-dig cyclization with successive ring opening under mild reaction conditions (Scheme 2). Scheme 1. Synthesis of Pyrroloquinolines and Indolizines (i) Metal-catalyzed synthesis of pyrrolo[1,2-a]quinolines and indolizines by Gevorgyan and co-workers

(ii) Iodine-mediated synthesis of indolizines by Kim and co-workers

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RESULTS AND DISCUSSION Previously, Larock and co-workers reported the synthesis of fused polycyclic compounds via palladium-catalyzed annulations which involved the electrophilic cyclization through the CH activation of adjacent aromatic carbon.18 As a part of our ongoing efforts in the synthesis of heterocycles19 by electrophilic cyclization of alkynes,20 we hypothesized the synthesis of polyheterocycles 5 from alkynyl pyranoquinoline 4 by C-C bond formation under proper reaction conditions (Scheme 2, route A). Scheme 2. Design of Tandem Strategy for the Synthesis of Heterocycles 5_9


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Our initial studies showed that reaction failed to afford the designed heterocycle 5, however a novel product 6a was isolated (Scheme 2, route B). The structure of the product 6a was unambiguously established as pyrrolo[1,2-a]quinoline by the X-ray crystallographic analysis21 (See Supporting Information Figure S1). Efforts to synthesize 6a directly from 4iodopyranoquinoline 2a require high catalyst loading and afforded the product 6a in low yield. The possible reason might be due to the formation of iodo reduced22 product. This developed methodology provides heterocycles with two carbonyl groups, which could be useful for the medicinal utility of the molecule.4e To identify the optimal conditions for the reaction, a number of reported catalysts for cyclization such as Ag(I), Cu(I), Pd(II) and I2 along with several organic solvents were examined in the reaction of 1-methoxy-3-phenyl-4-(phenylethynyl)-1H-pyrano[4,3-b]quinoline (4a) under various conditions (Table 1). When 5 mol % of Pd(OAc)2 were used as catalyst in CH2Cl2, no consumption of substrate 4a was observed after 5 h (Table 1, entry 1). Increasing the catalyst loading from 5 to 10 mol % made no effect on the substrate 4a even after 10 h (entry 2). PdCl2(PPh3)2 and CuI were also found ineffective for the reaction (entries 3 and 4). When Ag(I) salts like AgOTf was used, surprisingly product 6a was obtained in 90% yield (entry 5). Decreasing the catalyst loading from 10 to 5 mol % made no considerable effect on the yield of product 6a and the reaction was completed in 3 h (entries 6 and 7). Decrease in the catalyst loading from 5 to 2 mol % adversely effected the yield of the product 6a (entry 8). Longer reaction time also lead to the incomplete conversion of 4a and afforded the product 6a in 55% yield only (entry 9). From entries 9–13 in table 1 it is apparent that solvent has a significant influence on the reaction. CH2Cl2 and CHCl3 were found suitable for this reaction, THF afforded the product 6a in lower yield (entries 10 and 11), while no reaction was observed in protic 5 ACS Paragon Plus Environment


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solvents like EtOH and H2O (entries 12 and 13). Other silver-catalysts like AgOAc and AgNO3 were found effective and afforded the product 6a in 60 and 78% yields respectively (entries 14 and 15). After screening various metal-catalysts, Ag(I) catalyst was found to be most efficient to carry out this transformation. Table 1. Optimization of the Reaction Conditionsa

entry

solvent

catalyst

mol%

t (h)

1

CH2Cl2

Pd(OAc)2

5

5

2

CH2Cl2

Pd(OAc)2

10

10

yieldb 6a 8a 00 00

3

CH2Cl2

PdCl2(PPh3)2

10

10

00

-

4

CH2Cl2

CuI

10

10

00

-

5

CH2Cl2

AgOTf

10

5

90

-

6

CH2Cl2

AgOTf

5

5

90

-

7

CH2Cl2

AgOTf

5

3

90

-

8

CH2Cl2

AgOTf

2

3

45

-

9

CH2Cl2

AgOTf

2

5

55

-

10

CHCl3

AgOTf

5

3

86

-

11

THF

AgOTf

5

3

75

-

12 13

EtOH

AgOTf

5

3

00

-

H2O

AgOTf

5

3

00

-

14

CH2Cl2

AgOAc

5

3

60

-

15

CH2Cl2

AgNO3

5

3

78

16

CH2Cl2

I2

10

3

-

6

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17

CH2Cl2

I2

1c

3

-

45

18

CH2Cl2

I2

2c

3

-

70

19

CH2Cl2

I2

3c

3

-

81

20

CH2Cl2

I2

3c

10

-

81

a

Reactions were performed using 0.25 mmol of 4a, catalyst in 2.0 mL of solvent at 25 °C unless otherwise noted. b Isolated yield. c equiv. After optimizing the reaction conditions with metal-catalysts, we next examined the efficacy of iodine for this reaction. Use of catalytic amount of iodine was found ineffective (entry 16); however 1.0 equivalent of iodine afforded the 2-iodopyrrolo[1,2-a]quinoline 8a in 45% yield (entry 17). With 2.0 equivalent of iodine, product 8a was obtained in 70% yield (entry 18); while 3.0 equivalent of iodine afforded the product 8a in 85% yield with in 3 h (entry 19). A longer reaction time made no significant changes in the yield of product 8a (entry 20). We then investigated the substrate scope of the developed chemistry (Table 2). The substrate 4-alkynyl-pyrano[4,3-b]quinolines 4a–o and pyrano[4,3-b]pyridine 4p–t required for examining the scope of the reaction were readily prepared by the Sonogashira coupling of the 4iodopyrano[4,3-b]quinolines 2a–j with terminal alkynes 3. The substrate 2a–j required for this approach were readily prepared by electrophilic iodocyclization of ortho-alkynylaldehydes using reported procedure (Scheme 3).15b-c Scheme 3. Synthesis of 4-Iodopyrano[4,3-b]quinolines (2a–j) and 4-alkynyl-pyrano[4,3b]quinolines



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As shown in Table 2, the reaction was well tolerant towards a variety of R1, R2 and R3 substituents (entries 1–20). Substrates bearing aryl group at R2 afforded the desired product 6a– o, 6l in good to excellent yields (entries 1–12, 15). However, aliphatic substituents afforded the desired products 6m and 6n in lower yields and required longer reaction time (entries 13 and 14). The substrates 4m–n with aliphatic substituents were unstable; therefore they were used directly for the reaction without isolation. Alkynes bearing an electron-rich substituents at R3 provided the desired products 6b–c, 6e–g, 6i–k in 82–92% yield (entries 2–3, 5–7, 9–11). However, substrates 4h and 4l having n-alkyl substituted aryl group at R3 afforded the products 6h and 6l in comparatively lower yields (entries 8 and 12). The presence of OMe group at R1 made no significant effect on the yield of the desired product 6o (entry 15). To further examine the generality of the developed chemistry, pyrano[4,3-b]pyridines 4p–t were allowed to react under the optimized reaction conditions (entries 16–20). The electron-deficient aromatic ring of this substrate afforded the corresponding indolizines 7a–e in 75–80% yields. No significant effect on the yield of the product 7a was observed with substrate 4p having meta substituted aryl alkyne at R3 (entry 16). Table 2. Scope of the Developed Tandem Strategy for the Synthesis of Pyrrolo[1,2a]quinolines 6a–i and Indolizines 7a–ca

entry

substrate

product

yieldb 8


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OMe O

4a

6a

90

2

4b

6b

92

3

4c

6c

86

4

4d

6d

88

5

4e

6e

91

6

4f

6f

89

1

N Me



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7

4g

6g

85

8

4h

6h

83

9

4i

6i

82

10

4j

6j

85

6k

87

6l

80

11

12

4k

4l


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13

4m

6m

78c

6n

75c

6o

90

14

4n

15

4o

16

4p

7a

75

17

4q

7b

78

18

4r

7c

77



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19

4s

20

3t

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7d

80

7e

75

a

Unless otherwise specified, all reactions were performed with alkynyl pyranoquinoline 4 (0.25 mmol), AgOTf (5.0 mol %) in 2.0 mL of CH2Cl2 at 25 °C for 3–4 h. b Isolated yields. c reactions for 7–8 h. After obtaining successful results with Ag(I) catalyst, we have further extended the scope of this chemistry by employing iodine as an electrophile. To our delight, this electrophilic cyclization proceeded smoothly and afforded the iodo products 8a–j and 9a–b in good yields (Table 3). Substrate with electron-rich substitutents afforded the corresponding products 8a–h, 8j in 75–84% yields (entries 1–8, 10), while product 8i was obtained in 70% yield with alkyne 4n bearing cyclohexyl group at R2 (entry 9). Iodo-indolizines 9a–b were obtained in 72–75% yields using alkynes 4q and 4s (entries 11 and 12). Table 3. Synthesis of Pyrrolo[1,2-a]quinolines 8a–j and Indolizines 9a–ba

entry

substrate

product

yieldb 12


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1

4a

8a

81

2

4b

8b

84

3

4d

8c

80

4

4f

8d

82

5

4g

8e

78

6

4h

8f

75

8g

77

7

4u 13 ACS Paragon Plus Environment


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4j

8h

75

9

4n

8i

70

10

4o

8j

80

11

4q

9a

70

12

4s

9b

72

8

a

All reactions were performed with alkynyl pyranoquinoline 4 (0.25 mmol), I2 (3.0 equiv) in 2.0 mL of CH2Cl2 at 25 °C for 3–4 h. b Isolated yields. The formation of the desired iodocyclized compounds 8a–j and 9a–b were confirmed by their spectral data (1HNMR,

13

CNMR and HRMS) and finally by the X-ray crystallographic data of

compound 9b21 (See supporting Information Figure S2). To rationalize this tandem process, we proposed a plausible mechanism (Scheme 4). Presumably, the Ag metal coordinates with the triple bond of alkyne 4, to form intermediate P, similarly iodine forms iodonium intermediate P'. The formation of intermediate P and P' 14 ACS Paragon Plus Environment

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triggering the attack of pyridyl nitrogen on the triple bond which leads to the generation of cationic species Q and Q' via intramolecular 5-endo-dig cyclization.16b The cationic species Q and Q' then aromatize to form the oxonium intermediate R. Due to the instability of the intermediate R, it immediately converts into a more stable intermediate S by opening of pyran ring, which upon loss of the Me18c and MeI13f provided the product 6, 7 and 8, 9 respectively. Loss of the Me group is thought to occur during the aqueous workup, but the actual path for this step is unclear. Scheme 4. A Plausible Mechanism 4

I2

AgOTf 6,7

OMe O N

alkyne activation

8,9 + MeI

O Me

Ph

P'

OMe

Ph

N

I

O

I+

3

R

O R3

N


S

Ph

R3


Ag/I OMe

OMe ring opening

O N 3 Q' R

I

P Ag

O N

Ph cation stablization by oxygen

Ph

R3

OMe

Ag Q

O N R3

Ph R

Ag/I

With above results, we investigated further structural elaboration of the iodo-substituted pyrrolo[1,2-a]quinolines via palladium-catalyzed cross-coupling reactions. To this end, compound 8a was functionalized by applying palladium-catalyzed Suzuki23 and Heck24 coupling



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reactions to afford the corresponding products 11 and 13 in 75% and 70% yields, respectively (Scheme 5). Scheme 5. Pd-Catalyzed Cross-Coupling Reactions of 8a O

O 1.2 equiv Me Me N

1.2 equiv O N

11

MeO 10

B(OH)2

5 mol % Pd(PPh3)2Cl2 K2CO3 (2.5 equiv), Me DMF:H2O, 80 °C, 2 h

8a

12

O O

5 mol % Pd(PPh3)2Cl2 K3PO4 (2.5 equiv), DMF, 120 °C, 4 h

OMe

N

Me N 13 O

Me

Me

COMPUTATIONAL STUDIES In order to understand the site-selectivity for ring cyclization (Scheme 6) by C-C (path ′a′) or N-C (path ′b′) bond formation, quantum chemical calculations have been performed on the model system (4d; R2 = Ph, R3 = Ph). Scheme 6. Possible Site-Selective Electrophilic Cyclization

The fate of this reaction depends on the pre-reaction complex (PRC; complex of 4 and AgNO3), (Figure 2). In the formation of PRC 11.73 kcal/mol [in complexation of reactants (REC) 4 and AgNO3] energy is released. PRC may lead to two kinds of products, based on the attack of pyridine N (C-N bond formation) and/or phenyl CH (C-C bond formation). The 3D 16 ACS Paragon Plus Environment

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structures of PRC, transition states (TS-1 and TS-2) and the intermediates (INT-1 and INT-2) on the reaction paths ′a′ and ′b′ respectively were obtained using B3LYP optimization. In PRC, Ag metal is almost symmetrically attached to both alkynyl carbons (C1 and C2) but in the transition states, it is preferably attached to the C2 atom. Therefore, this C2 adapts sp2 character, leading to an increased proximity between C1 and pyridine N or CH.

1.85 Å

TS‐1 C‐C bond formation C2 C1

INT‐1

2.38 Å

2.34 Å

PRC 2.11 Å

TS‐2 C‐N bond formation

INT‐2

Figure 2. 3D Geometry (B3LYP/6-31+G(d)) of PRC, transition states (TS-1 and TS-2) and intermediates (INT-1 and INT-2) (LanL2DZ basis set is used for Ag metal). Figure 3 shows that the formation of INT-2 is exothermic by 7.70 kcal/mol with an energy barrier of 9.01 kcal/mol. On the other hand, the energy barrier for the formation of INT-1 is 17 ACS Paragon Plus Environment


larger by 22.30 kcal/mol and lead to an endothermic INT-1. This establishes that the formation of a five membered ring through C-N bond formation is the preferred path as per thermodynamic as well as kinetic controls. TS‐1

35 30

Energy kcal/mol

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25

INT‐1

31.31

20 15

REC

C‐C interaction

TS‐2

C‐N‐interaction

10 5

9.01

0 ‐5

0

2

PRC

‐10

4

6

8

10

INT‐2

Figure 3. Potential energy surface for PRC, transition states (TS-1 and TS-2) and intermediates (INT-1 and INT-2) (B3LYP/6-31+(d)). CONCLUSIONS In summary, we have demonstrated the facile synthesis of substituted pyrrolo[1,2-a]quinolines and indolizines via electrophilic cyclization followed by ring opening under mild reaction conditions using silver catalyst as well as inexpensive iodine. This chemistry involved the preferential nucleophilic attack of the pyridyl nitrogen over aryl ring onto the adjacent alkyne carbon to form 5-endo-dig cyclized products. The formation of 5-endo-dig cyclized products by the site-selective electrophilic cyclization was supported by the quantum chemical calculations between C-C (ΔEa = 31.31 kcal/mol) and C-N (ΔEa = 9.01 kcal/mol) bond of the substrate 4d. The structure of the products were confirmed by the X-ray crystallographic studies. The cyclized products 8 and 9 embedded with iodo group could be a useful handle for further elaboration 18 ACS Paragon Plus Environment

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using palldium-catalyzed coupling reactions. From a synthetic point of view, the net transformation involves a one-step conversion of simple, and readily available starting materials into interesting class of heterocyclic compounds. This chemistry is expected to find application in organic synthesis in general, and in the construction of a variety of compounds. Further investigations of this synthetic protocol are under progress and will be reported in due course. EXPERIMENTAL PROCEDURES General Method: 1H NMR (400 MHz) and

13

C NMR (100 MHz) spectra were recorded in

CDCl3. Chemical shifts for carbons are reported in ppm from tetramethylsilane and are referenced to the carbon resonance of the solvent. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd = doublet of doublet), coupling constants in Hertz, and integration. High-resolution mass spectra were recorded with electrospray mass spectrometer. Crystal structure analysis was accomplished on single crystal Xray diffractometer. TLC analysis was performed on commercially prepared 60 F254 silica gel plates and visualized by either UV irradiation or by staining with I2. All purchased chemicals were used as received. The starting material 2 were prepared by electrophilic iodocyclization using reported procedure.15b-c The structure and purity of known starting materials 2a−b, 2d−g,15a−b,2h and 2j13e were confirmed by comparison of their physical and spectral data (1H NMR and 13C NMR) with those reported in literature. 3-(4-Butylphenyl)-4-iodo-1-methoxy-1H-pyrano[4,3-b]quinoline (2c). The product was obtained as light brown crystals (423.9 mg, 90% yield): mp 78–80 °C; 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.8, 1H), 19 ACS Paragon Plus Environment


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7.59 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 7.6 Hz, 1H), 7.21–7.18 (m, 2H), 6.16 (s, 1H), 3.65 (s, 3H), 2.61 (t, J = 7.7 Hz, 2H), 1.60–1.54 (m, 2H), 1.35–1.29 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H);

13

C

NMR (100 MHz, CDCl3) δ 157.8, 148.8, 148.0, 145.0, 134.1, 133.1, 130.2, 129.9, 129.4, 127.9, 127.5, 127.4, 126.3, 121.9, 100.4, 56.5, 35.6, 33.3, 22.4, 13.9; HRMS (ESI) calcd for [C23H22INO2] requires [M]+ 471.0695, found [M]+ 471.0698. 8-Iodo-5-methoxy-7-(p-tolyl)-5H-pyrano[4,3-b]pyridine (2i). The product was obtained as semi-solid; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 5.8 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.51(d, J = 7.3 Hz, 1H), 7.27 (s, 1H), 7.26–7.22 (m, 2H), 6.09 (s, 1H), 3.67 (s, 3H), 2.43 (s, 3H); 13

C NMR (100 MHz, CDCl3) δ 156.1, 150.7, 148.2, 139.9, 133.7, 133.3, 129.8, 128.6, 122.2,

99.9, 75.9, 56.1, 21.5; HRMS (ESI) calcd for [C16H14INO2] requires [M]+ 379.0069, found [M]+ 379.0070. General Procedure for the Synthesis of Alkynyl-pyrano[4,3-b]quinoline and Pyridine 4a–u. To a solution of 4-iodopyranoquinoline 1 (0.25 mmol) in DMF were added 5 mol% of PdCl2(PPh3)2. The reaction vial was then sealed and flushed with nitrogen. Then 3.0 equiv of DIPA and 1.2 equiv of alkyne were added. The reaction was then stirred at 80°C until TLC revealed complete conversion of the starting material. The solution was allowed to cool and diluted with H2O and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated, and purified by column chromatography to afford the corresponding product. The structure and purity of known starting materials 4f−g15a were confirmed by comparison of their physical and spectral data (1H NMR and

13

C NMR) with those reported in

literature. 1-Methoxy-4-(phenylethynyl)-3-(p-tolyl)-1H-pyrano[4,3-b]quinoline (4a). The product was obtained as semi-solid (151.2 mg, 75% yield); 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.8 Hz, 20 ACS Paragon Plus Environment

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1H), 8.11 (d, J = 8.0 Hz, 2H), 7.99 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.65 (td, J = 1.4 and 6.6 Hz, 1H), 7.51 (dd, J = 1.4 and 8.0 Hz, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.29–7.21 (m, 5H), 6.25 (s, 1H), 3.68 (s, 3H), 2.36 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 159.5, 149.1, 149.0, 140.7, 132.9,

131.4, 131.3, 130.0, 129.0, 128.7, 128.2, 127.7, 127.6, 127.0, 126.0, 124.2, 122.0, 100.3, 95.7, 85.0, 56.4, 21.5; HRMS (ESI) calcd for [C28H21NO2] requires [M]+ 403.1572, found [M]+ 403.1575. 1-Methoxy-4-((4-methoxyphenyl)ethynyl)-3-(p-tolyl)-1H-pyrano[4,3-b]quinoline (4b). The product was obtained as a pale yellow solid (168.8 mg, 78 %): mp 80–82°C; 1H NMR (400 MHz, CDCl3) δ 8.24–8.18 (m, 3H), 8.06 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.53–7.49 (m, 3H), 7.29 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 6.32 (s, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 149.0, 140.7, 132.9, 131.4, 130.8, 130.0, 129.8, 129.0, 128.6, 127.6, 127.1, 126.0, 122.1, 116.5, 114.3, 113.8, 100.3, 95.9, 83.2, 56.4, 55.3, 21.6; HRMS (ESI) calcd for [C29H23NO3] requires [M]+ 433.1678, found 433.1679. 1-Methoxy-4-(thiophen-3-ylethynyl)-3-(p-tolyl)-1H-pyrano[4,3-b]quinoline (4c). The product was obtained as dark brown solid (149.2 mg, 73% yield): mp 100–102°C; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.8 Hz, 1H), 8.17 (d, J = 8.0 Hz, 2H), 8.07 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 6.6 Hz, 1H), 7.54–7.53 (m, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.30–7.28 (m, 3H), 7.26–7.24 (m, 1H), 6.31 (s, 1H), 3.74 (s, 3H), 2.42 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ

160.3, 148.9, 140.9, 133.1, 131.1, 130.2, 129.9, 129.8, 129.6, 129.0, 128.7, 128.1, 127.6, 127.0, 126.1, 124.9, 123.2, 122.6, 122.0, 100.3, 90.9, 84.0, 56.5, 21.6; HRMS (ESI) calcd for [C26H19NO2S] requires [M]+ 409.1136, found [M]+ 409.1140.



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Page 22 of 44

1-Methoxy-3-phenyl-4-(phenylethynyl)-1H-pyrano[4,3-b]quinoline (4d). The product was obtained as semi-solid (136.1 mg, 70% yield); 1H NMR (400 MHz, CDCl3) 8.21–8.16 (m, 3H), 8.00 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.66 (td, J = 1.4 and 7.3 Hz, 1H), 7.48 (dd, J = 1.4 and 6.5 Hz, 2H), 7.43–7.41 (m, 4H), 7.29–7.23 (m, 3H), 6.27 (s, 1H), 3.69 (s, 3H); 13C NMR (100 MHz, CDCl3)

160.0, 148.9, 148.7, 134.3, 132.9, 131.4, 130.3, 130.1, 129.9, 129.1, 128.2, 127.9,

127.8, 127.7, 126.2, 124.1, 121.9, 100.8, 100.5, 95.6, 84.7, 56.5; HRMS (ESI) calcd for [C27H19NO2] requires [M]+ 389.1416, found [M]+ 389.1422. 1-Methoxy-4-((4-methoxyphenyl)ethynyl)-3-phenyl-1H-pyrano[4,3-b]quinoline

(4e).

The

product was obtained as semi-solid (136.1 mg, 65% yield); 1H NMR (400 MHz, CDCl3) δ 8.22– 8.16 (m, 3H), 8.02 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.66 (td, J = 1.4 and 5.8 Hz, 1H), 7.45-7.40 (m, 6H), 6.80 (dd, J = 6.7 and 2.0 Hz, 2H), 6.27 (s, 1H), 3.76 (s, 3H), 3.69 (s, 3H);

13

C NMR

(100 MHz, CDCl3) δ 159.3, 149.0, 134.3, 133.0, 132.9, 130.2, 130.1, 129.8, 129.0, 127.9, 127.6, 127.1, 126.1, 122.0, 116.3, 113.8, 101.0, 100.4, 95.9, 83.2, 56.4, 55.3; HRMS (ESI) calcd for [C28H21NO3] requires [M]+ 419.1521, found [M]+ 419.1522. 4-((4-Butylphenyl)ethynyl)-1-methoxy-3-phenyl-1H-pyrano[4,3-b]quinoline

(4h).

The

product was obtained as semi-solid (151.3 mg, 68% yield); 1H NMR (400 MHz, CDCl3) δ 8.27– 8.25 (m, 2H), 8.22 (d, J = 8.7 Hz, 1H), 8.06 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.71 (td, J = 1.4 and 8.7 Hz, 1H), 7.50–7.45 (m, 6H), 7.14 (d, J = 8.0 Hz, 2H), 6.32 (s, 1H), 3.75 (s, 3H), 2.60 (t, J = 7.6 Hz, 2H), 1.59–1.57 (m, 2H), 1.39–1.33 (m, 2H), 0.92 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.5, 149.1, 149.0, 142.9, 134.2, 132.9, 131.3, 130.2, 130.0, 129.8, 129.0, 128.3, 127.9, 127.6, 127.1, 126.1, 122.0, 121.2, 101.1, 100.4, 96.0, 84.0, 56.4, 35.6, 33.4, 22.3, 13.9; HRMS (ESI) calcd for [C31H27NO2] requires [M]+ 445.2042, found [M]+ 445.2046.


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3-(4-Butylphenyl)-1-methoxy-4-((4-methoxyphenyl)ethynyl)-1H-pyrano[4,3-b]quinoline (4i). The product was obtained as semi-solid (154.7 mg, 65% yield); 1H NMR (400 MHz, CDCl3)

1

H NMR (400 MHz, CDCl3) δ 8.24–8.20 (m, 3H), 8.03 (s, 1H), 7.78 (d, J = 8.0 Hz,

1H), 7.70 (t, J = 8.0 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.46 (t, J = 7.3 Hz, 1H ), 7.29 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.28 (s, 1H), 3.80 (s, 3H), 3.72 (s, 3H) 2.68 (t, J = 7.32 Hz, 2H), 1.68–1.60 (m, 2H), 1.43–1.33 (m, 2H), 0.94 (t, J = 7.32 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 149.2, 144.5, 132.9, 132.7, 131.5, 130.0, 129.7, 129.5, 129.0, 128.8, 128.1, 127.8, 127.6, 127.0, 126.0, 125.9, 122.0, 116.4, 113.9, 100.1, 95.7, 83.5, 56.4, 55.3, 35.6, 33.3, 22.3, 13.9; HRMS (ESI) calcd for [C32H29NO3] requires [M+H]+ 476.2225, found [M+H]+ 476.2225. 3-(4-Butylphenyl)-1-methoxy-4-(thiophen-3-ylethynyl)-1H-pyrano[4,3-b]quinoline (4j). The product was obtained as semi-solid (139.8 mg, 62% yield); 1H NMR (400 MHz, CDCl3) δ 8.17– 8.11 (m, 3H), 8.00 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.65 (td, J = 1.4 and 5.8 Hz, 1H), 7.45 (d, J = 2.9 Hz, 1H), 7.41 (d, J = 7.3 Hz, 1H), 7.23–7.20 (m, 3H), 7.18 (s, 1H), 6.25 (s, 1H), 3.68 (s, 3H), 2.61 (t, J = 6.9 Hz, 2H), 1.59–1.56 (m, 2H), 1.34–1.26 (m, 2H), 0.89–0.85 (m, 3H);

13

C

NMR (100 MHz, CDCl3) δ 160.0, 149.1, 149.0, 145.7, 133.0, 131.5, 130.1, 129.9, 129.7, 129.0, 128.0, 127.6, 127.0, 126.1, 124.9, 123.2, 122.0, 114.1, 100.3, 91.0, 84.2, 56.4, 35.6, 33.3, 22.4, 13.9; HRMS (ESI) calcd for [C29H25NO2S] requires [M]+ 451.1606, found 451.1606. 3-(4-(tert-Butyl)phenyl)-1-methoxy-4-(p-tolylethynyl)-1H-pyrano[4,3-b]quinoline (4k). The product was obtained as semi-solid (149.1 mg, 65% yield); 1H NMR (400 MHz, CDCl3) δ 8.34– 8.30 (m, 3H), 8.08 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.77 (t, J = 7.3 Hz, 1H), 7.59–7.56 (m, 4H), 7.52 (t, J = 6.7 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 6.35 (s, 1H), 3.79 (s, 3H), 2.42 (s, 3H), 1.44 (s, 9H);

13

C NMR (100 MHz, CDCl3) δ 159.5, 153.6, 149.1, 137.8, 132.9, 131.4, 131.2, 130.0, 23



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129.7, 129.1, 128.9, 128.6, 127.6, 127.0, 125.0, 124.8, 122.8, 121.1, 100.2, 96.0, 84.3, 56.4, 34.9, 31.1, 21.5; HRMS (ESI) calcd for [C32H29NO2] requires [M+H]+ 460.2276, found [M+H]+ 460.2275. 3-(4-(tert-Butyl)phenyl)-4-((4-butylphenyl)ethynyl)-1-methoxy-1H-pyrano[4,3-b]quinoline (4l). The product was obtained as semi-solid (162.8 mg, 65% yield); 1H NMR (400 MHz, CDCl3) δ 8.34–8.29 (m, 3H), 8.08 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.58–7.55 (m, 4H), 7.54–7.50 (m, 1H), 7.23 (d, J = 8.0 Hz, 2H), 6.34 (s, 1H), 3.78 (s, 3H), 2.67 (t, J = 7.3 Hz, 2H), 1.70–1.63 (m, 2H), 1.44–1.43 (m, 9H), 1.41–1.39 (m, 2H), 0.99 (t, J = 8.08 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 153.6, 149.1, 142.8, 132.9, 131.4, 131.2, 130.0, 129.7, 128.8, 128.6, 128.4, 128.1, 127.6, 127.0, 125.9, 125.0, 122.0, 121.3, 100.1, 96.1, 84.3, 56.4, 35.6, 34.9, 33.3, 31.2, 22.3, 13.9; HRMS (ESI) calcd for [C35H35NO2] requires [M+H]+ 502.2746, found [M+H]+ 502.2746. 3-(4-Ethylphenyl)-1,8-dimethoxy-4-(phenylethynyl)-1H-pyrano[4,3-b]quinoline (4o). The product was obtained as a semi-solid (167.6 mg, 75% yield); 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.0 Hz, 2H), 8.06 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 7.50 (d, J = 6.5 Hz, 2H), 7.32–7.22 (m, 6H), 7.00 (d, J = 2.2 Hz, 1H), 6.21 (s, 1H), 3.84 (s, 3H), 3.66 (s, 3H), 2.66 (q, J = 7.3 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 157.4, 146.8, 146.7, 144.7, 131.9, 131.4, 131.2, 130.3, 128.9, 128.0, 127.6, 127.3, 123.1, 122.9, 122.1, 105.3, 100.1, 99.6, 95.5, 84.6, 56.2, 55.3, 28.7, 15.1; HRMS (ESI) calcd for [C30H25NO3] requires [M+H]+ 448.1912, found [M+H]+ 448.1913. 5-Methoxy-7-phenyl-8-(m-tolylethynyl)-5H-pyrano[4,3-b]pyridine (4p). The product was obtained as a semi-solid (105.9 mg, 60% yield); 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 3.6 Hz, 1H), 8.22–8.20 (m, 2H), 7.59 (d, J = 5.8 Hz, 1H), 7.47–7.43 (m, 3H), 7.34–7.29 (m, 2H), 24 ACS Paragon Plus Environment

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7.24 (t, J = 6.6 Hz, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.19 (s, 1H), 3.67 (s, 3H), 2.30 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 158.5, 150.9, 148.8, 141.5, 137.7, 134.2,

133.5, 132.1, 130.1, 128.9, 128.7, 128.5, 128.0, 127.9, 125.0, 123.5, 122.0, 121.9, 99.9, 95.8, 84.0, 56.1, 21.2; HRMS (ESI) calcd for [C24H19NO2] requires [M]+ 353.1416, found [M]+ 353.1420 5-Methoxy-8-(phenylethynyl)-7-p-tolyl-5H-pyrano[4,3-b]pyridine (4q). The product was obtained as a semi-solid (107.6 mg, 61% yield); 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 5.1 Hz, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.54–7.52 (m, 2H), 7.46–7.41 (m, 2H), 7.26–7.13 (m, 5H), 6.13 (s, 1H), 3.62 (s, 3H), 2.35 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 158.5, 151.1, 149.0,

140.4, 133.1, 131.4, 131.2, 128.8, 128.6, 128.4, 128.0, 127.98, 127.8, 127.7, 126.1, 124.0, 121.9, 121.6, 99.9, 99.4, 95.3, 84.8, 56.0, 21.3; HRMS (ESI): calcd for [C24H19NO2] requires [M]+ 353.1416, found [M]+ 353.1426. 5-Methoxy-7-(4-methoxyphenyl)-8-(phenylethynyl)-5H-pyrano[4,3-b]pyridine

(4r).

The

product was obtained as a semi-solid (116.2 mg, 63% yield); 1H NMR (400 MHz, CDCl3) δ 8.69 (dd, J = 5.1 and 1.4 Hz, 1H), 8.15 (d, J = 8.8 Hz, 2H), 7.52 (dd, J = 7.3 and 1.4 Hz, 1H), 7.46 (dd, J = 8.0 and 1.4 Hz, 2H), 7.24–7.20 (m, 3H), 7.17–7.14 (m, 1H), 6.91 (d, J = 8.8 Hz, 2H), 6.12 (s, 1H), 3.81 (s, 3H), 3.62 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 161.2, 158.6, 151.0,

149.2, 133.2, 131.5, 130.7, 128.1, 127.7, 126.3, 122.0, 121.5, 113.3, 99.9, 98.5, 95.3, 84.9, 56.1, 55.4; HRMS (ESI) calcd for [C24H19NO3] requires [M]+ 369.1365, found [M]+ 369.1368. 5-Methoxy-7-(4-methoxyphenyl)-8-(p-tolylethynyl)-5H-pyrano[4,3-b]pyridine

(4s).

The

product was obtained as a a semi-solid (124.4 mg, 65% yield); 1H NMR (400 MHz, CDCl3) δ 8.73 (dd, J = 2.2 and 5.1 Hz, 1H), 8.21 (dd, J = 2.2 and 6.5 Hz, 2H), 7.56 (dd, J = 1.4 and 7.3 Hz, 1H), 7.41 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 5.1 Hz, 1H), 7.10 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.7 25 ACS Paragon Plus Environment


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Hz, 2H), 6.16 (s, 1H), 3.85 (s, 3H), 3.66 (s, 3H), 2.32 (s, 3H);

13

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161.0, 158.0, 151.1, 149.3, 137.7, 133.1, 131.3, 130.6, 128.9, 126.6, 121.9, 121.4, 121.0, 113.3, 99.9, 98.8, 95.4, 84.2, 56.0, 55.3, 21.5; HRMS (ESI) calcd for [C25H21NO3] requires [M]+ 383.1521, found [M]+ 383.1524. 5-Methoxy-7-(4-methoxyphenyl)-8-(thiophen-3-ylethynyl)-5H-pyrano[4,3-b]pyridine

(4t).

The product was obtained as a semi-solid (112.5 mg, 60% yield); 1H NMR (400 MHz, CDCl3) δ 8.68 (dd, J = 1.4 and 5.1, 1H), 8.13 (dd, J = 2.2 and 6.6, 2H), 7.53–7.50 (m, 2H), 7.42 (d, J = 2.9 Hz, 1H), 7.19–7.12 (m, 2H), 6.91 (d, J = 8.7, 2H), 6.12 (s, 1H), 3.80 (s, 3H), 3.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.0, 158.2, 151.1, 149.1, 133.1, 130.5, 129.9, 129.4, 129.2, 128.0, 127.7, 126.5, 124.8, 123.0, 121.8, 121.5, 113.3, 99.9, 90.4, 84.2, 56.0, 55.3; HRMS (ESI) calcd for [C22H17NO3S]+ requires [M]+ 375.0929, found 375.0923. 3-(4-Butylphenyl)-1-methoxy-4-(phenylethynyl)-1H-pyrano[4,3-b]quinoline

(4u).

The

product was obtained as a semi-solid (160.2 mg, 72% yield); 1H NMR (400 MHz, CDCl3) δ 8.14-8.12 (m, 3H), 7.98 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 6.6 Hz, 2H), 7.41 (t, J = 8.0 Hz, 1H), 7.29-7.22 (m, 5H), 6.24 (s, 1H), 3.68 (s, 3H), 2.62 (d, J = 7.7 Hz, 2H), 1.60–1.56 (m, 2H), 1.34–1.29 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H);

13

C NMR (100

MHz, CDCl3) δ 160.2, 148.9, 148.6, 145.7, 133.2, 131.1, 130.2, 128.9, 128.0, 127.9, 127.62, 127.59, 126.9, 126.0, 123.9, 121.8, 100.0, 99.7, 95.5, 84.5, 56.3, 35.4, 33.2, 22.1, 13.7; HRMS (ESI) calcd for [C31H27NO2]+ requires [M]+ 445.2042, found 445.2041. General Procedure for the Synthesis of 3-Benzoyl-1-aryl Pyrrolo[1,2-a]quinoline-4carbaldehyde 6a–o: To a vial 4-alkynl pyranoquinoline 3 (0.25 mmol) and 5 mol% AgOTf was added in DCM. The reaction vial was then sealed and stirred at room temperature until TLC revealed complete conversion of the starting material. The solution was diluted with H2O and 26 ACS Paragon Plus Environment

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then extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated, and purified by column chromatography to afford the corresponding product. 3-(4-Methylbenzoyl)-1-phenylpyrrolo[1,2-a]quinoline-4-carbaldehyde (6a). The product was obtained as a yellow solid (87.5 mg, 90% yield): mp 150–152 °C; 1H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 7.94–7.89 (m, 3H), 7.86 (dd, J = 1.4 and 6.6 Hz, 1H), 7.52–7.48 (m, 6H), 7.39 (td, J = 0.7 and 6.5 Hz, 1H), 7.32–7.28 (m, 3H), 6.97 (s, 1H), 2.44 (s, 3H);

13

C NMR (100 MHz,

CDCl3) δ 191.7, 188.9, 143.0, 136.6, 134.7, 134.2, 131.0, 130.8, 130.0, 129.8, 129.4, 129.0, 128.9, 128.6, 128.2, 128.1, 125.0, 124.2, 120.3, 118.3, 116.8, 21.6; HRMS (ESI) calcd for [C27H19NO2] requires [M]+ 389.1416, found [M]+ 389.1416. 1-(4-Methoxyphenyl)-3-(4-methylbenzoyl)pyrrolo[1,2-a]quinoline-4-carbaldehyde (6b). The product was obtained as yellow crystals (96.3 mg, 92% yield): mp 164–166 °C; 1H NMR (400 MHz, CDCl3) δ 10.18 (s,1H), 7.83 (d, J = 8.0 Hz, 3H), 7.77 (dd, J = 5.8 and 1.4 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.33–7.29 (m, 3H), 7.25 (dd, J = 8.8 and 1.4 Hz, 1H), 7.24–7.20 (m, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.86 (s, 1H), 3.83 (s, 3H), 2.36 (s, 3H);

13


191.7, 189.0, 160.0, 142.9, 140.7, 136.7, 135.1, 132.9, 130.8, 130.0, 129.8, 128.6, 127.9, 127.6, 126.3, 126.0, 124.9, 122.0, 120.0, 118.0, 116.5, 114.3, 100.3, 55.4, 21.6; HRMS (ESI) calcd for [C28H21NO3] requires [M]+ 419.1521, found [M]+ 419.1520. 3-(4-Methylbenzoyl)-1-(thiophen-3-yl)pyrrolo[1,2-a]quinoline-4-carbaldehyde

(6c).

The

product was obtained as yellow crystals (84.9 mg, 86% yield): mp 180–182 °C; 1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 7.93 (s, 1H), 7.90–7.85 (m, 3H), 7.57 (d, J = 8.0 Hz, 1H), 7.50– 7.48 (m, 2H), 7.41–7.37 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.12 (dd, J = 5.1 and 1.4 Hz, 1H), 7.00 (s, 1H), 2.44 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 191.4, 188.9, 143.4, 136.8, 135.1, 27



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134.2, 131.0, 130.8, 130.3, 129.8, 129.0, 128.8, 128.1, 126.6, 125.6, 125.1, 125.0, 124.2, 120.5, 117.6, 116.6, 21.6; HRMS (ESI) calcd for [C25H17NO2S] requires [M]+ 395.0980, found [M]+ 395.0985. 3-Benzoyl-1-phenylpyrrolo[1,2-a]quinoline-4-carbaldehyde (6d). The product was obtained as a yellow solid (82.5 mg, 88% yield): mp 150–152 °C; 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 7.93–7.89 (m, 3H), 7.80 (d, J = 7.3 Hz, 1H), 7.50 (t, J = 7.3 Hz, 1H), 7.45–7.40 (m, 8H), 7.32 (t, J = 6.6 Hz, 1H), 7.24 (td, J = 1.4 and 8.8 Hz, 1H), 6.90 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 191.8, 188.9, 139.3, 134.8, 134.1, 132.2, 131.1, 130.8, 130.1, 129.6, 129.4, 128.9, 128.7, 128.3, 128.2, 125.0, 124.3, 120.4, 118.3, 116.6. HRMS (ESI) calcd for [C26H17NO2] requires [M]+ 375.1259, found [M]+ 375.1261. 3-Benzoyl-1-(4-methoxyphenyl)pyrrolo[1,2-a]quinoline-4-carbaldehyde (6e). The product was obtained as a yellow solid (92.1 mg, 91% yield): mp 160–162 °C; 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 7.92 (d, J = 7.3 Hz, 2H), 7.86 (s, 1H), 7.80 (dd, J = 1.4 and 7.3 Hz, 1H), 7.52–7.48 (m, 2H), 7.44–7.40 (m, 2H), 7.34–7.30 (m, 3H), 7.26 (dd, J = 1.8 and 8.7 Hz, 1H), 6.94 (dd, J = 2.2 and 6.6 Hz, 2H), 6.86 (s, 1H), 3.83 (s, 3H);

13


191.8, 189.0, 159.9, 139.4, 135.0, 132.1, 131.0, 130.9, 130.8, 130.1, 129.6, 128.3, 128.2, 128.1, 126.4, 125.0, 124.3, 120.1, 118.1, 116.4, 114.3, 55.4; HRMS (ESI) calcd for [C27H19NO3] requires [M]+ 405.1365, found [M]+ 405.1366. 3-Benzoyl-1-(p-tolyl)pyrrolo[1,2-a]quinoline-4-carbaldehyde (6f). The product was obtained as yellow crystals (86.5 mg, 89% yield): mp 130–132 °C; 1H NMR (400 MHz, CDCl3) δ 10.3 (s, 1H), 7.98 (d, J = 7.3 Hz, 2H), 7.94 (m, 1H), 7.87 (d, J = 7.3 Hz, 1H), 7.58–7.56 (m, 2H), 7.50– 7.47 (m, 2H), 7.41–7.34 (m, 3H), 7.32–7.28 (m, 3H), 6.94 (s, 1H), 2.46 (s, 3H); 13C NMR (100 28 ACS Paragon Plus Environment

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MHz, CDCl3) δ 191.8, 188.9, 139.3, 138.7, 134.9, 132.1, 131.2, 130.8, 130.0, 129.6, 129.4, 129.3, 128.2, 125.0, 124.9, 124.3, 120.3, 120.2, 118.1, 116.5, 21.5; HRMS (ESI) calcd for [C27H19NO2] requires [M]+ 389.1416, found [M]+ 389.1417. 3-Benzoyl-1-(thiophen-3-yl)pyrrolo[1,2-a]quinoline-4-carbaldehyde (6g). The product was obtained as a orange solid (80.9 mg, 85% yield): mp 168–170 °C; 1H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 7.92–7.88 (m, 3H), 7.80 (dd, J = 1.4 and 7.3 Hz, 1H), 7.52–7.48 (m, 2H), 7.44– 7.40 (m, 4H), 7.37–7.29 (m, 2H), 7.60 (dd, J = 1.4 and 4.4 Hz, 1H), 6.93 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 191.6, 188.9, 139.3, 135.0, 134.1, 132.2, 130.8, 130.4, 129.6, 128.8, 128.3, 128.1, 126.6, 125.7, 125.1, 125.0, 124.2, 120.6, 117.6, 116.3; HRMS (ESI) calcd for [C24H15NO2S] requires [M]+ 381.0823, found [M]+ 381.0825. 3-Benzoyl-1-(4-butylphenyl)pyrrolo[1,2-a]quinoline-4-carbaldehyde (6h). The product was obtained as a yellow solid (89.4 mg, 83% yield): mp 140–142 °C; 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 7.90 (dd, J = 2.2 and 6.6 Hz, 2H), 7.86 (s, 1H), 7.78 (dd, J = 1.4 and 7.3 Hz, 1H), 7.50–7.45 (m, 2H), 7.40 (t, J = 8.0 Hz, 2H), 7.32–7.29 (m, 3H), 7.24–7.20 (m, 3H), 6.87 (s, 1H), 2.63 (t, J = 8.0 Hz, 2H), 1.64–1.54 (m, 2H), 1.36–1.31 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H);

13

C

NMR (100 MHz, CDCl3) δ 191.8, 189.0, 143.7, 139.4, 134.9, 132.1, 131.3, 131.2, 130.8, 130.0, 129.6, 129.3, 128.9, 128.3, 128.2, 128.1, 125.0, 124.3, 118.2, 116.4, 35.5, 33.5, 22.3, 13.9; HRMS (ESI) calcd for [C30H25NO2] requires [M]+ 431.1885, found [M]+ 431.1892. 3-(4-Butylbenzoyl)-1-(4-methoxyphenyl)pyrrolo[1,2-a]quinoline-4-carbaldehyde (6i). The product was obtained as yellow crystals (94.5 mg, 82% yield): mp 170–172 °C; 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 7.93–7.91 (m, 3H), 7.85 (d, J = 7.3 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.41–7.36 (m, 3H), 7.33–7.28 (m, 3H), 7.01 (d, J = 8.7 Hz, 2H), 6.94 (s, 1H), 3.90 (s, 3H), 29 ACS Paragon Plus Environment


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2.68 (t, J = 7.6 Hz, 2H), 1.65–1.62 (m, 2H), 1.40–1.33 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H);

13

C

NMR (100 MHz, CDCl3) δ 191.7, 189.0, 159.9, 147.9, 136.8, 135.0, 130.9, 130.0, 129.8, 128.4, 128.2, 127.8, 126.5, 124.9, 124.3, 120.1, 118.0, 116.6, 114.3, 55.4, 35.7, 33.3, 22.3, 13.9; HRMS (ESI) calcd for [C31H27NO3] requires [M]+ 461.1991, found [M]+ 461.1992. 3-(4-Butylbenzoyl)-1-(thiophen-3-yl)pyrrolo[1,2-a]quinoline-4-carbaldehyde

(6j).

The

product was obtained as a yellow solid (92.8 mg, 85% yield): mp 106–108 °C; 1H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 7.94–790 (m, 3H), 7.87 (dd, J = 2.2 and 8.0 Hz, 1H), 7.58 (d, J = 6.6 Hz, 1H), 7.50–7.48 (m, 2H), 7.43–7.37 (m, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.13 (dd, J = 3.6 and 5.1 Hz, 1H), 7.01 (s, 1H), 2.69 (t, J = 7.3 Hz, 2H), 1.68–1.60 (m, 2H), 1.42–1.37 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 191.7, 188.9, 148.0, 136.9, 135.0, 134.2, 131.1, 130.8, 130.3, 129.8, 128.8, 128.4, 128.1, 128.0, 126.6, 125.6, 125.0, 124.2, 120.5, 117.6, 116.4, 35.7, 33.3, 22.3, 13.9; HRMS (ESI) calcd for [C28H23NO2S] requires [M]+ 437.1449, found 437.1450. 3-(4-(tert-Butyl)benzoyl)-1-(p-tolyl)pyrrolo[1,2-a]quinoline-4-carbaldehyde

(6k).

The

product was obtained as a yellow solid (96.7 mg, 87% yield): mp 180–182 °C; 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 7.89–7.86 (m, 3H), 7.79 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.33–7.29 (m, 3H), 7.26–7.20 (m, 3H), 6.89 (s, 1H), 2.39 (s, 3H), 1.29 (s, 9H);

13

C NMR (100 MHz, CDCl3) δ 191.6, 189.1, 155.9, 138.6, 136.5, 134.8, 131.3,

131.1, 130.8, 129.9, 129.7, 129.6, 129.3, 128.3, 127.8, 125.3, 124.9, 124.2, 120.3, 118.2, 116.7, 35.1, 31.1, 21.4; HRMS (ESI) calcd for [C31H27NO2] requires [M]+ 445.2042, found [M]+ 445.2043. 3-(4-(tert-Butyl)benzoyl)-1-(4-butylphenyl)pyrrolo[1,2-a]quinoline-4-carbaldehyde (6l). The product was obtained as yellow solid (97.4 mg, 80% yield): mp 158–160 °C; 1H NMR (400 30 ACS Paragon Plus Environment

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MHz, CDCl3) δ 10.27 (s, 1H), 7.94–7.91 (m, 3H), 7.84 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 9.5 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.37–7.34 (m, 3H), 7.30–7.25 (m, 3H), 6.95 (s, 1H), 2.67–2.69 (m, 2H), 169–1.62 (m, 2H), 1.42–1.34 (m, 2H), 1.32 (s, 9H), 0.95 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 191.6, 189.0, 155.9, 143.6, 136.5, 134.9, 131.4, 131.1, 130.8, 129.9, 129.7, 129.4, 128.9, 128.3, 127.8, 125.3, 124.9, 124.3, 120.3, 118.2, 116.6, 35.5, 35.1, 33.4, 31.2, 22.4, 14.0; HRMS (ESI) calcd for [C34H33NO2] requires [M+H]+ 488.2589, found [M+H]+ 488.2589. 3-Pentanoyl-1-phenylpyrrolo[1,2-a]quinoline-4-carbaldehyde

(6m).

The

product

was

obtained as a brown solid (69.2 mg, 78% yield): mp 128–130 °C; 1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 7.81 (s, 1H), 7.76 (dd, J = 1.4 and 8.0 Hz, 1H), 7.49–7.36 (m, 6H), 7.30 (t, J = 7.3 Hz, 1H), 7.21 (dd, J = 1.4 and 7.3 Hz, 1H), 7.05 (s, 1H), 2.88 (t, J = 5.2 Hz, 2H), 1.72–1.69 (m, 2H), 1.39–1.33 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 197.2, 189.5, 134.4, 134.3, 131.5, 130.7, 129.8, 129.4, 129.1, 128.9, 128.7, 127.4, 125.0, 124.3, 118.3, 118.2, 116.9, 40.5, 27.0, 22.6, 14.1; HRMS (ESI) calcd for [C24H21NO2] requires [M+H]+ 356.1650, found [M+H] + 356.1650. 3-(Cyclohexanecarbonyl)-1-phenylpyrrolo[1,2-a]quinoline-4-carbaldehyde

(6n).

The

product was obtained as a pale yellow solid (71.4 mg, 75% yield): mp 118–120 °C; 1H NMR (400 MHz, CDCl3) δ 10.3 (s, 1H), 7.79 (s, 1H), 7.75 (dd, J = 1.4 and 7.3 Hz, 1H), 7.42 (s, 5H), 7.39 (d, J = 8.8 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 7.22-7.18 (m, 1H), 7.04 (s, 1H), 3.11-3.05 (m, 1H), 1.91–1.88 (m, 2H), 1.81–1.77 (m, 2H), 1.67–1.64 (m, 1H), 1.54–1.50 (m, 2H), 1.34–1.25 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 200.5, 189.2, 134.4, 134.3, 131.5, 131.1, 130.7, 129.7, 129.4, 129.1, 128.9, 128.7, 127.3, 125.0, 124.3, 118.1, 118.0, 116.1, 45.0, 29.7, 29.5, 25.9; HRMS (ESI) calcd for [C26H23NO2] requires [M]+ 381.1729, found [M]+ 381.1731.



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3-(4-Ethylbenzoyl)-7-methoxy-1-phenylpyrrolo[1,2-a]quinoline-4-carbaldehyde (6o). The product was obtained as orange crystals (97.4 mg, 90% yield): mp 178–180 °C; 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.88 (s, 1H), 7.46 (s, 6H), 7.41 (d, J = 9.5 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 6.89 (dd, J = 2.9 and 9.5 Hz, 1H), 3.87 (s, 3H), 2.72 (q, J = 7.3 Hz, 2H), 1.27 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 192.3, 189.1, 156.3, 149.0, 136.9, 134.2, 131.0, 130.5, 129.9, 129.4, 129.2, 128.8, 128.6, 127.8, 127.4, 125.6, 120.3, 119.6, 119.0, 116.4, 111.3, 55.6, 28.9, 15.3; HRMS (ESI) calcd for [C29H23NO3] requires [M]+ 433.1678, found [M]+ 433.1680. General Procedure for the Synthesis of 1-Benzoyl-3-aryl-indolizine-8-carbaldehyde 7a–e. To a vial 4-alkynl pyranoquinoline 3 (0.25 mmol) and 5 mol% AgOTf was added in DCM. The reaction was then sealed and stirred at room temperature until TLC revealed complete conversion of the starting material. The solution was diluted with H2O and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated, and purified by column chromatography to afford the corresponding product. 1-Benzoyl-3-(m-tolyl)indolizine-8-carbaldehyde (7a). The product was obtained as a yellow solid (63.5 mg, 75% yield): mp 100-102 °C; 1H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 8.40 (d, J = 7.3 Hz, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 7.3 Hz, 1H), 7.50–7.46 (m, 1H), 7.43– 7.39 (m, 2H), 7.32 (t, J = 8.0 Hz, 1H), 7.24–7.23 (m, 2H), 7.18 (t, J = 4.4 Hz, 1H), 6.84 (t, J = 7.3 Hz, 1H), 7.05 (s, 1H), 2.35 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 191.0, 190.0, 139.9,

139.2, 133.1, 131.7, 130.1, 129.7, 129.6, 129.4, 129.2, 128.2, 127.6, 127.5, 125.9, 119.8, 119.7, 114.0, 112.8, 112.7, 21.4; HRMS (ESI) calcd for [C23H17NO2] requires [M+H]+ 340.1337, found [M+H]+ 340.1337.


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1-(4-Methylbenzoyl)-3-phenylindolizine-8-carbaldehyde (7b). The product was obtained as a brown solid (66.1 mg, 78% yield): mp 140–142 °C; 1H NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 8.39 (dd, J = 1.4 and 6.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.65 (dd, J = 1.4 and 6.6 Hz, 1H), 7.46–7.45 (m, 4H), 7.40–7.38 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.09 (s, 1H), 6.83 (t, J = 6.6 Hz, 1H), 2.37 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 191.0, 190.0, 142.6, 137.1, 132.8, 130.4,

129.7, 129.3, 129.0, 128.7, 127.4, 125.7, 119.7, 114.0, 112.7, 21.6; HRMS (ESI) calcd for [C23H17NO2] requires [M]+ 339.1259, found [M]+ 339.1260. 1-(4-Methoxybenzoyl)-3-phenylindolizine-8-carbaldehyde (7c). The product was obtained as a orange solid (67.4 mg, 76% yield): mp 110–112 °C; 1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 8.38 (d, J = 6.6 Hz, 1H ), 790–7.88 (m, 2H), 7.62 (d, J = 6.6 Hz, 1H ), 7.45–7.44 (m, 4H), 7.38–7.35 (m, 1H), 7.09 (s, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.81 (t, J = 7.3 Hz, 1H), 3.81 (s, 3H); 13

C NMR (100 MHz, CDCl3) δ 190.1, 189.8, 162.7, 139.2, 132.7, 132.3, 131.8, 130.4, 129.3,

129.0, 128.9, 128.7, 127.4, 127.0, 125.6, 119.4, 114.3, 114.0, 113.5, 112.5, 55.4; HRMS (ESI) calcd for [C23H17NO3] requires [M]+ 355.1208, found [M]+ 355.1209. 1-(4-Methoxybenzoyl)-3-p-tolylindolizine-8-carbaldehyde (7d). The product was obtained as yellow solid (73.8 mg, 80% yield): mp 130–132 °C; 1H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 8.36 (d, J = 5.8 Hz, 1H), 7.88 (dd, J = 2.2 and 6.6 Hz, 2H), 7.61 (dd, J = 1.4 and 5.8 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.06 (s, 1H), 6.90 (dd, J = 2.2 and 6.6 Hz, 2H), 6.80 (t, J = 7.3 Hz, 1H), 3.81 (s, 3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.1, 189.9, 162.7, 138.8, 132.6, 132.4, 132.0, 131.8, 129.9, 129.0, 128.9, 128.4, 127.4, 125.4, 119.2, 114.2, 113.5, 112.4, 55.5, 21.3; HRMS (ESI): calcd for [C24H19NO3] requires [M]+ 369.1365, found [M]+ 369.1366.



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1-(4-Methoxybenzoyl)-3-(thiophen-3-yl)indolizine-8-carbaldehyde (7e). The product was obtained as brown solid (63.1 mg, 75% yield): mp 160–162 °C; 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 8.38 (d, J = 5.8 Hz, 1H), 7.89 (dd, J = 2.2 and 6.6 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.47-7.45 (m, 1H), 7.43-7.42 (m, 1H), 7.22 (dd, J = 1.4 and 5.1Hz, 1H), 7.11 (s, 1H), 6.92 (d, J = 9.5 Hz, 2H), 6.85 (t, J = 7.3 Hz, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.1, 189.8, 162.7, 132.6, 132.4, 131.8, 130.7, 129.0, 127.5, 125.5, 124.0, 122.3, 119.5, 114.1, 113.6, 112.6, 55.5; HRMS (ESI) calcd for [C21H15NO3S] requires [M]+ 361.0773, found 361.0774. General Procedure for the Synthesis of 3-Benzoyl-2-iodo-1-aryl-pyrrolo[1,2-a]quinoline-4carbaldehyde 8a–j. To a vial 4-alkynl pyranoquinoline 3 (0.25 mmol) and 3.0 equiv of I2 was added in DCM. The reaction vial was then sealed and stirred at room temperature until TLC revealed complete conversion of the starting material. The solution was washed with saturated solution of Na2S2O3 and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated, and purified by column chromatography to afford the corresponding product. 2-Iodo-3-(4-methylbenzoyl)-1-phenylpyrrolo[1,2-a]quinoline-4-carbaldehyde

(8a).

The

product was obtained as a brown solid (104.2 mg, 81% yield): mp 160–162 °C; 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 7.3 Hz, 1H), 7.72 (s, 1H), 7.56–7.54 (m, 3H), 7.44–7.42 (m, 2H), 7.34–7.30 (m, 1H), 7.25–7.24 (m, 3H), 7.21–7.19 (m, 1H), 2.39 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 193.2, 188.0, 143.8, 136.0, 135.0, 134.4,

132.4, 132.2, 131.2, 131.0, 130.8, 130.5, 130.2, 129.4, 129.3, 128.8, 127.8, 126.1, 125.7, 124.9, 123.0, 121.3, 117.9, 21.8; HRMS (ESI) calcd for [C27H18INO2] requires [M]+ 515.0382, found [M]+ 515.0382.


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2-Iodo-1-(4-methoxyphenyl)-3-(4-methylbenzoyl)pyrrolo[1,2-a]quinoline-4-carbaldehyde (8b). The product was obtained as brown crystals (114.4 mg, 845 yield): mp 178–180 °C; 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.35–7.33 (m, 3H), 7.31–7.28 (m, 3H), 7.25 (s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 3.92 (s, 3H), 2.39 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 193.3, 188.0, 160.3, 143.8, 136.0, 135.1,

132.4, 132.3, 132.1, 131.0, 130.7, 130.2, 129.3, 126.4, 126.1, 125.5, 124.8, 123.0, 121.1, 117.8, 114.7, 55.3, 21.8; HRMS (ESI) calcd for [C28H20INO3] requires [M]+ 545.0488, found [M]+ 545.0489. 3-Benzoyl-2-iodo-1-phenylpyrrolo[1,2-a]quinoline-4-carbaldehyde (8c). The product was obtained as a dark yellow solid (100.2 mg, 80% yield): mp 154–156 °C; 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 7.90 (d, J = 7.3 Hz, 2H), 7.73 (d, J = 7.3 Hz, 1H), 7.68 (s, 1H), 7.51–7.47 (m, 4H), 7.41–7.37 (m, 4H), 7.28 (t, J = 7.2 Hz, 1H), 7.20–7.15 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 193.5, 187.9, 138.5, 135.0, 134.4, 132.9, 132.6, 132.5, 131.2, 131.0, 130.8, 130.0, 129.5, 129.3, 128.5, 126.1, 125.7, 124.9, 123.0, 121.2, 118.0; HRMS (ESI) calcd for [C26H16INO2] requires [M+H]+ 502.0304, found [M+H]+ 502.0305. 3-Benzoyl-2-iodo-1-p-tolylpyrrolo[1,2-a]quinoline-4-carbaldehyde (8d). The product was obtained as a brown solid (105.5 mg, 82% yield): mp 168–170 °C; 1H NMR (400 MHz, CDCl3)

δ 9.80 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 7.3 Hz, 1H), 7.74 (s,1H), 7.57 (t, J = 7.0 Hz, 1H), 7.48-7.45 (m, 2H), 7.39–7.37 (m, 2H), 7.34–7.29 (m, 5H), 2.51 (s, 3H);

13

C NMR (100

MHz, CDCl3) δ 192.7, 187.1, 138.6, 137.6, 134.1, 131.9, 131.6, 130.4, 130.0, 129.8, 129.1, 127.6, 125.2, 124.6, 123.9, 122.0, 120.1, 117.1, 20.7; HRMS (ESI) calcd for [C27H18INO2] requires [M]+ 515.0382, found [M]+ 515.0341.



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3-Benzoyl-2-iodo-1-(thiophen-3-yl)pyrrolo[1,2-a]quinoline-4-carbaldehyde (8e). The product was obtained as a dark yellow solid (98.6 mg, 78% yield): mp 160–162 °C; 1H NMR (400 MHz, CDCl3) δ 9.72 (s, 1H), 7.89 (dd, J = 1.4 and 8.0 Hz, 2H), 7.75–7.73 (m, 1H), 7.68 (s, 1H), 7.53– 7.49 (m, 2H), 7.48–7.46 (m, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.33–7.29 (m, 2H), 7.28–7.24 (m, 1H), 7.06 (dd, J = 1.6 and 5.1 Hz, 1H);

13

C NMR (100 MHz, CDCl3) δ 193.4, 187.9, 138.5,

135.1, 133.8, 132.9, 132.7, 131.3, 130.7, 130.0, 129.2, 128.5, 127.8, 127.1, 126.0, 125.8, 125.0, 123.0, 121.1, 117.5; HRMS (ESI) calcd for [C24H14INO2S] requires [M]+ 506.9790, found 506.9793. 3-Benzoyl-1-(4-butylphenyl)-2-iodopyrrolo[1,2-a]quinoline-4-carbaldehyde

(8f).

The

product was obtained as a dark yellow solid (104.4 mg, 75% yield): mp 158–160 °C; 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 7.96 (d, J = 7.3 Hz, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.46 (t, J = 6.4 Hz, 2H), 7.39–7.33 (m, 5H), 7.25 (s, 2H), 2.76 (t, J = 8.8 Hz, 2H), 1.77–1.69 (m, 2H), 1.46–1.41 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 193.8, 188.0, 144.5, 138.5, 135.1, 132.9, 132.4, 131.5, 131.6, 131.0, 130.7, 130.1, 129.3, 128.5, 126.1, 125.6, 124.8, 123.0, 121.1, 118.0, 35.6, 33.3, 22.4, 14.0; HRMS (ESI) calcd for [C30H24INO2] requires [M]+ 557.0852, found [M]+ 557.0859. 3-(4-Butylbenzoyl)-2-iodo-1-phenylpyrrolo[1,2-a]quinoline-4-carbaldehyde

(8g).

The

product was obtained as a yellow solid (107.2 mg, 77% yield): mp 170–172°C; 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 7.3 Hz, 1H), 7.72 (s, 1H), 7.56–7.55 (m, 3H), 7.44–7.42 (m, 2H), 7.32 (t, J = 6.6 Hz, 1H), 7.27-7.21 (m, 4H), 2.65(t, J = 7.6 Hz, 2H), 1.65–1.57 (m, 2H), 1.38–1.32 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H);

13

C NMR (100

MHz, CDCl3) δ 193.3, 187.9, 148.7, 136.2, 135.0, 134.4, 132.4, 131.9, 131.2, 130.9, 130.8,


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130.2, 129.5, 129.3, 128.6, 126.2, 125.8, 124.9, 123.0, 121.3, 118.6, 35.8, 33.1, 22.4, 13.9; HRMS (ESI) calcd for [C30H24INO2]+ requires m/z 557.0852, found 557.0853. 3-(4-Butylbenzoyl)-2-iodo-1-(thiophen-3-yl)pyrrolo[1,2-a]quinoline-4-carbaldehyde

(8h).

The product was obtained as a brown solid (105.5 mg, 75% yield): mp 210–212 °C; 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.10 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.60–7.54 (m, 2H), 7.38 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 7.23–7.21 (m, 2H), 7.18 (s, 3H), 2.60 (t, J = 7.3 Hz, 2H), 1.56– 1.54 (m, 2H), 1.34–1.28 (m, 2H), 0.89–0.80 (m, 3H);

13

C NMR (100 MHz, CDCl3) δ 189.5,

186.0, 150.5, 147.9, 146.4, 140.2, 137.2, 136.7, 134.7, 130.1, 129.5, 128.7, 128.6, 128.5, 127.2, 127.1, 126.2, 123.9, 121.3, 118.2, 35.6, 33.4, 22.3, 13.9; HRMS (ESI) calcd for [C28H22INO2S] requires [M]+ 563.0416, found [M]+ 563.0416. 3-(Cyclohexanecarbonyl)-2-iodo-1-phenylpyrrolo[1,2-a]quinoline-4-carbaldehyde (8i). The product was obtained as a yellow crystals (88.7 mg, 70% yield): mp 120–122 °C; 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.73–7.70 (m, 2H), 7.51–7.49 (m, 3H), 7.34–7.32 (m, 2H), 7.26 (t, J = 7.3 Hz, 1H), 7.16–7.14 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 3.03–2.97 (m, 1H), 2.03–2.00 (m, 2H), 1.77–1.76 (m, 2H), 1.55–1.46 (m, 2H), 1.27–1.19 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 204.6, 188.3, 134.8, 134.7, 132.6, 132.0, 131.2, 130.9, 130.7, 129.5, 129.3, 126.6, 124.9, 123.1, 122.5, 118.0, 52.0, 28.5, 26.0; HRMS (ESI) calcd for [C26H22INO2] requires [M]+ 507.0695, found [M]+ 507.0696. 3-(4-Ethylbenzoyl)-2-iodo-7-methoxy-1-phenylpyrrolo[1,2-a]quinoline-4-carbaldehyde (8j). The product was obtained as a orange crystals (111.8 mg, 80% yield): mp 140–142 °C; 1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.66 (s, 1H), 7.56–7.54 (m, 3H), 7.43–7.41 (m, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 2.9 Hz, 1H), 7.12 (d, J = 9.5 Hz, 1H), 6.84 (dd, J = 2.9 and 9.5 Hz, 1H), 3.83 (s, 3H), 2.70 (q, J = 7.3 Hz, 2H), 1.25 (t, J = 7.3 Hz, 37 ACS Paragon Plus Environment


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3H);

13

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C NMR (100 MHz, CDCl3) δ 193.4, 188.0, 156.1, 149.9, 136.2, 134.4, 131.9, 131.3,

131.2, 130.3, 129.4, 129.3, 128.0, 126.5, 125.6, 124.3, 121.0, 119.4, 119.3, 111.6, 55.6, 29.0, 15.0. HRMS (ESI) calcd for [C29H22INO3] requires [M]+ 559.0644, found 559.0641. General Procedure for the Synthesis of 1-Benzoyl-2-iodo-3-aryl-indolizine-8-carbaldehyde 9a–b. To a vial 4-alkynl pyranoquinoline 3 (0.25 mmol) and 3.0 equiv of I2 was added in DCM. The reaction was then stirred at room temperature until TLC revealed complete conversion of the starting material. The solution was washed with saturated solution of Na2S2O3 and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated, and purified by column chromatography to afford the corresponding product. 2-Iodo-1-(4-methylbenzoyl)-3-phenylindolizine-8-carbaldehyde

(9a).

The

product

was

obtained as a yellow solid (81.3 mg, 70% yield): mp 80–82 °C; 1H NMR (400 MHz, CDCl3) δ 9.7 (s, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.51–7.47 (m, 2H), 7.45–7.42 (m, 3H), 7.37 (d, J = 6.5 Hz, 1H), 7.20–7.18 (m, 1H), 6.62 (t, J = 6.9 Hz,1H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 193.0, 188.0, 143.7, 136.2, 131.0, 130.2, 129.9, 129.5, 129.3, 128.7, 128.3, 126.9, 126.5, 118.4, 110.5, 21.8; HRMS (ESI) calcd for [C23H16INO2] requires [M]+ 465.0226, found [M]+ 465.0227. 2-Iodo-1-(4-methoxybenzoyl)-3-p-tolylindolizine-8-carbaldehyde (9b). The product was obtained as a orange crystals (89.1 mg, 72% yield): mp 102–104 °C; 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 8.09 (dd, J = 1.4 and 5.8 Hz, 1H), 7.88 (dd, J = 2.2 and 6.6 Hz, 2H), 7.41 (dd, J = 1.4 and 6.6 Hz, 1H), 7.36 (s, 4H), 6.91 (dd, J = 2.2 and 6.5 Hz, 2H), 6.65 (t, J = 6.9 Hz, 1H), 3.85 (s, 3H), 2.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 192.3, 188.1, 163.4, 139.6, 132.4,


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131.8, 130.9, 130.0, 128.8, 128.3, 126.9, 126.5, 118.2, 113.8, 110.4, 55.4, 21.5; HRMS (ESI) calcd for [C24H18INO3] requires [M]+ 495.0331, found [M]+ 495.0335. General Procedure for the Synthesis of Suzuki coupling Product 11. To a vial was added the 8a (0.20 mmol), 1.2 equiv of (4-methoxyphenyl)boronic acid 10, 10 mol % Pd(PPh3)2Cl2, K2CO3 (2.5 equiv) and DMF:H2O (4:1) (2.0 mL). The reaction vial was then sealed and flushed with nitrogen, and then heated to 80 °C until TLC revealed complete conversion of the starting material. The solution was allowed to cool and diluted with H2O and then extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by column chromatography to afford the corresponding product. 2-(4-Methoxyphenyl)-3-(4-methylbenzoyl)-1-phenylpyrrolo[1,2-a]quinoline-4carbaldehyde (11). The product was obtained as a brown solid (74.2 mg, 75% yield): mp 200– 201 °C; 1H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 7.74 (t, J = 7.3 Hz, 3H), 7.68 (s, 1H), 7.32 (t, J = 7.3 Hz, 1H), 7.28–7.21 (m, 5H), 7.16–7.10 (m, 4H), 6.82 (d, J = 8.8 Hz, 2H), 6.47 (d, J = 8.8 Hz, 2H), 3.58 (s, 3H), 2.34 (s, 3H);

13

C NMR (100 MHz, CDCl3) δ 194.4, 188.4, 158.0,

139.4, 138.4, 135.7, 132.3, 131.6, 131.3, 131.1, 130.7, 130.4, 130.3, 129.6, 128.4, 128.0, 127.1, 125.7, 125.1, 124.2, 123.5, 118.2, 117.8, 113.0, 54.9, 21.4; HRMS (ESI) calcd for [C34H25NO3] requires [M]+ 495.1834, found [M]+ 495.1834. General Procedure for the Synthesis of Heck coupling Product 13. To a vial was added the 8a (0.20 mmol), 1.2 equiv of N,N-dimethylacrylamide (12), 10 mol % Pd(PPh3)2Cl2, K3PO4 (2.5 equiv) and DMF (2.0 mL). The reaction vial was then sealed and flushed with nitrogen, and then heated to 80 °C until TLC revealed complete conversion of the starting material. The solution was allowed to cool and diluted with H2O and then extracted with EtOAc. The combined organic 39 ACS Paragon Plus Environment


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layers were dried over MgSO4, concentrated, and purified by column chromatography to afford the corresponding product. (E)-3-(4-Formyl-3-(4-methylbenzoyl)-1-phenylpyrrolo[1,2-a]quinolin-2-yl)-N,Ndimethylacrylamide (13). The product was obtained as a brown solid (68.0 mg, 70% yield): mp 160–162 °C; 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.49–7.45 (m, 1H), 7.39–7.35 (m, 2H), 7.27–7.24 (m, 5H), 7.22–7.19 (m, 3H), 6.21 (d, J = 16.1 Hz, 1H), 2.76 (s, 3H), 2.53 (s, 3H), 2.41 (s, 3H); 13C NMR (400 MHz, CDCl3) δ 194.9, 188.2, 166.8, 139.6, 139.1, 135.6, 133.9, 133.3, 133.0, 132.5, 131.0, 130.8, 130.2, 129.5, 129.3, 128.7, 126.8, 126.8, 124.7, 124.6, 122.4, 123.3, 119.4, 118.2, 116.0, 29.7, 29.6, 20.7; HRMS (ESI) calcd for [C32H26N2O3] requires [M+H]+ 487.2023, found [M+H]+ 487.2021. ACKNOWLEDGMENT The Research work was supported by Department of Science and Technology (SR/S1/OC66/2010). T.A., S.K. and D.K.D. are thankful to CSIR for fellowship. Our sincere thanks to Sushil Kumar, University of Delhi, for his kind help in solving X-ray crystallographic data. Supporting Information Available: Experimental procedures and copies of HRMS, 1H and 13C NMR spectra for all new compounds. CIF for compound 5a. This material is available free of charge via the internet at http://pubs.acs.org. (1) (a) Chen, Z.; Ding, Q.; Yu, X.; Wu, J. Adv. Synth. Catal. 2009, 351, 1692. (b) Oh, C. H.; Karmakar, S.; Park, H. S.; Ahn Y. C.; Kim, J. W. J. Am. Chem. Soc. 2010, 132, 1792. (c) Barluenga, J.; Diéguez, A.; Fernández, A.; Rodríguez F.; Fañanás, F. J. Angew. Chem. Int. 40 ACS Paragon Plus Environment

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Site-Selective Electrophilic Cyclization and Subsequent Ring-Opening

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